Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice
Wenwen Cheng, … , Darleen Sandoval, Martin G. Myers Jr.
Wenwen Cheng, … , Darleen Sandoval, Martin G. Myers Jr.
Published March 17, 2020
Citation Information: JCI Insight. 2020;5(7):e134359. https://doi.org/10.1172/jci.insight.134359.
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Research Article Endocrinology Metabolism

Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice

Abstract

Leptin receptor–expressing (LepRb-expressing) neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and that produce the food intake–suppressing PPG cleavage product glucagon-like peptide-1 [GLP1]) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgfl mouse lines, along with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgfl early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgfl blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.

Authors

Wenwen Cheng, Ermelinda Ndoka, Chelsea Hutch, Karen Roelofs, Andrew MacKinnon, Basma Khoury, Jack Magrisso, Ki Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen Sandoval, Martin G. Myers Jr.

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Figure 5

GLP1NTS neurons require Ppg to mediate the suppression of food intake.

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GLP1NTS neurons require Ppg to mediate the suppression of food intake. R...
Representative images of DREADD-hM3Dq-mCherry (purple) and FOS-IR (green) in CNO-treated (1 mg/kg i.p., 2 hours) Ppgcre (A) and PpgGLP1-NTSKO (PpgPpgKO) (B) mice subjected to the injection of AAVhM3Dq into the NTS (Ppg-Dq and PpgPpgKO-Dq mice, respectively). All panels are representative of n ≥ 3 similar images. AP, area postrema; cc, central canal. Scale bars: 150 μm. (C) Food intake in Ppg-Dq and PpgPpgKO-Dq mice during the first 4 hours of the dark cycle with chow or HFD, as indicated; n = 19 (chow) or 9 (HFD) in Ppg-Dq and n = 8 (both chow and HFD) in PpgPpgKO-Dq groups. (D) Food intake in vehicle-treated (Veh-treated) or CNO-treated (1 mg/kg i.p.) Ppg-Dq and PpgPpgKO-Dq mice following an overnight fast; n = 13, 5, and 8 in Veh, Ppg-Dq, and PpgPpgKO-Dq groups, respectively. (E and F) Daily food intake (E) and body weight (F) relative to baseline during multiday treatment with CNO (1 mg/kg, i.p., bid); n = 10, 8, and 8 in Veh, Ppg-Dq, and PpgPpgKO-Dq groups, respectively. Data are from both sexes; for data separated by sex, see Supplemental Figure 2, A–D. Data are shown as mean ± SEM. Two-way ANOVA with Sidak’s multiple comparisons test was performed for chow and HCD conditions (separately) in C. Two-way ANOVA with Tukey’s multiple comparisons test was performed for D–F. Different letters indicate difference (P < 0.05) in C. (D–F) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus Veh. ##P < 0.01, ####P < 0.0001 for Ppg-Dq versus PpgPpgKO-Dq.